NM_001455.4:c.32T>G

Variant names:

• chr6-108561240-T-G
• rs1191293561
• NM_001455.4:c.32T>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4 BS2

The NM_001455.4(FOXO3):​c.32T>G​(p.Leu11Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000354 in 1,412,056 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000035 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FOXO3 NM_001455.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.888
• Publications: 1 publications found

Genes affected

FOXO3 (HGNC:3821): (forkhead box O3) This gene belongs to the forkhead family of transcription factors which are characterized by a distinct forkhead domain. This gene likely functions as a trigger for apoptosis through expression of genes necessary for cell death. Translocation of this gene with the MLL gene is associated with secondary acute leukemia. Alternatively spliced transcript variants encoding the same protein have been observed. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38798982).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001455.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXO3	NM_001455.4	MANE Select	c.32T>G	p.Leu11Arg	missense	Exon 1 of 3	NP_001446.1	O43524-1
	FOXO3	NM_201559.3		c.32T>G	p.Leu11Arg	missense	Exon 2 of 4	NP_963853.1	O43524-1
	FOXO3	NM_001415150.1		c.32T>G	p.Leu11Arg	missense	Exon 2 of 3	NP_001402079.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXO3	ENST00000406360.2	TSL:1 MANE Select	c.32T>G	p.Leu11Arg	missense	Exon 1 of 3	ENSP00000385824.1	O43524-1
	FOXO3	ENST00000343882.10	TSL:1	c.32T>G	p.Leu11Arg	missense	Exon 2 of 4	ENSP00000339527.6	O43524-1
	FOXO3	ENST00000898147.1		c.32T>G	p.Leu11Arg	missense	Exon 2 of 4	ENSP00000568206.1

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151736 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000354 AC: 5 AN: 1412056 Hom.: 0 Cov.: 32 AF XY: 0.00000572 AC XY: 4 AN XY: 698698

African (AFR) AF: 0.00 AC: 0 AN: 31678

American (AMR) AF: 0.00 AC: 0 AN: 37770

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25114

East Asian (EAS) AF: 0.00 AC: 0 AN: 36656

South Asian (SAS) AF: 0.00 AC: 0 AN: 80590

European-Finnish (FIN) AF: 0.0000206 AC: 1 AN: 48430

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4068

European-Non Finnish (NFE) AF: 0.00000367 AC: 4 AN: 1089276

Other (OTH) AF: 0.00 AC: 0 AN: 58474

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000659 AC: 1 AN: 151736 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74064

African (AFR) AF: 0.00 AC: 0 AN: 41302

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5094

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10550

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67920

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.081	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	D
Eigen	Benign	0.035
Eigen_PC	Benign	0.028
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.42	T
M_CAP	Pathogenic	0.92	D
MetaRNN	Benign	0.39	T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.89
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.84	N
REVEL	Uncertain	0.37
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.57	T
Polyphen		0.91	P
Vest4		0.39
MutPred		0.13		Loss of sheet (P = 0.0817)
MVP		0.95
ClinPred		0.16	T
GERP RS		2.4
PromoterAI		-0.096	Neutral
Varity_R		0.30
gMVP		0.32
Mutation Taster		=79/21	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1191293561; hg19: chr6-108882443;